clinical trial of phenformin in combination with braf inhibitor + mek inhibitor for patients with braf-mutated melanoma

Conditions: Melanoma

Summary: the purpose of this study is to test whether it is safe to give phenformin with the standard drug combination of one of 3 fda-approved combinations of braf inhibitor + mek inhibitor which are standard treatments for patients with metastatic melanoma whose melanoma has a mutation in a gene called braf.


Eligibility criteria:
inclusion criteria: * ajcc (2009) stage iv melanoma, or stage iii melanoma not curable by surgery and which is progressing or in patients whom neo-adjuvant treatment is deemed acceptable. patients must have at least 1 target lesion measurable by recist 1.1 criteria. * the melanoma must harbor an activating braf v600 mutation. prior therapy with a braf and/or mek inhibitor is allowed in the dose-escalation phase only. however, patients who discontinued previous raf inhibitor due to intolerance of the drug rather than due to progression will not be eligible. * histologic proof of melanoma reviewed and confirmed by the treating institution. the melanoma must have a documented brafv600e or brafv600k mutation by genotyping or ihc12 performed by a clia certified laboratory. at msk, the diagnostic molecular pathology laboratory has developed and implemented a targeted capture-based next-generation dna sequencing assay, msk-impacttm, to profile all protein-coding exons and selected introns from 410 oncogenes and tumor suppressor genes in formalin-fixed paraffin embedded tissues (cheng, d.t., et al., j mol diagn, 2015. 17(3): p. 251-64). msk-impacttm has been approved by the ny state department of health to be run as a clinical assay in the clia-compliant diagnostic molecular pathology laboratory. msk-impacttm is capable of detecting mutations, copy number alterations, and structural variations. braf exon15 was captured by the msk-impacttm panel and the c.1799t\>a (p.v600e) mutation was fully validated as per nys requirements. detailed results of the validation of this mutation were included in the validation package submitted to ny state department of health. * at mgh, samples will be tested using a multiplex polymerase chain reaction (pcr) technology called anchored multiplex pcr (amp) for single nucleotide variant (snv) and insertion/deletion (indel) detection in genomic dna using next generation sequencing (ngs). briefly, genomic dna was isolated from a formalin-fixed paraffin embedded tumor specimen is sheared with the covaris m220 instrument, followed by end-repair, adenylation, and ligation with an adapter. a sequencing library targeting hotspots and exons in 39 genes (including braf, exons 11 and 15) is generated using two hemi-nested pcr reactions. illumina miseq 2 x 147 base paired-end sequencing results are aligned to the hg19 human genome reference using bwa-mem (li h and durbin r. bioinformatics 2009;25(14):1754-60). mutect (cibulskis k, et al. nat biotechnol 2013;31(3):213-9) and a laboratory-developed insertion/deletion analysis algorithm are used for snv and indel variant detection, respectively. this assay has been validated to detect snv and indel variants at 5% allelic frequency or higher in target regions with sufficient read coverage. this test was developed, and its performance characteristics were determined by the mgh center for integrated diagnostics. * patients must be adequately recovered from surgery, radiation therapy, or any surgical complications prior to enrollment. * age ≥ 18 years old. * ecog performance status of 0-2. * the ability to swallow pills and otherwise follow the protocol. * patients with treated cns metastases will be eligible if not symptomatic the cns disease has been stable for a minium of 6 weeks and the patient requires less than or equal to the equivalent of 2 mg/day of dexamethasone. * patients must have adequate organ and marrow function as defined below: * absolute neutrophil count ≥1.5 k/mcl * platelets ≥100 k/mcl * hemoglobin ≥ 9.0 g/dl * total bilirubin ≤ 1.2 x institutional upper limit of normal (uln) or ≤ 3.0 x institutional uln if the patient has gilbert's syndrome * ast (sgot) and alt (sgpt) ≤ 1.2 x institutional upper limit of normal (uln) * creatinine ≤ 1.4 mg/dl exclusion criteria: * type i or type ii diabetes * a history of renal failure (unless recovered for at least 6 months), lactic acidosis, recurrent or severe hypoglycemia, or significant chronic obstructive lung disease. patients will not be excluded for reversible episodes of elevated creatinine due to hypovolemia. * acute or chronic liver or renal disease. * concurrent use of hypoglycemic agents or any systemic therapy for melanoma. palliative limited-field radiation therapy will be allowed * current use of a prohibited medication. * vemurafenib * avoid inducers and inhibitors of cyp3a4 * careful with drugs metabolized by ctp1a2 (clozapam, olanzapine, fluvoxamine, haloperidol, theophylline, caffeine). * encorafenib * avoid inducers and inhibitors of cyp3a4 * avoid drugs that increase qtc interval * dabrafenib * avoid inducers and inhibitors of cyp3a4 or cyp2ca8 (refer to appendix c for specific drugs). * presence of conditions that will interfere significantly with the absorption of drugs. * a history of known glucose-6-phosphate dehydrogenase (g6pd) deficiency. * pregnant and/or lactating women * a prior or concurrent metastatic second malignancy within 3 years, even if it does not require active therapy. for example, patients with concomitant indolent b-cell malignancies will not be eligible. patients with a prior resected in-situ or stage i malignancy felt to be cured will be eligible. * other uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. new york heart association class ≥2 will be an exclusion criterion. * qtc interval \> 500 msec unless a bundle branch block is also present. * patients with brain metastases unless they meet the criteria of section 6.1.8. * patients currently receiving other anti-melanoma treatment. toxicities attributable to any prior therapy must have resolved to grade 1 or better prior to enrollment. grade 2 endocrinopathies, except diabetes, that are ongoing from prior immunotherapy will not exclude the patient as long as the patient is on appropriate replacement doses of hormone. * patients receiving steroid treatment exceeding replacement dosing * in the dose expansion phase of the trial, prior treatment with a braf inhibitor will be an exclusion criterion. this includes prior adjuvant dabrafenib/trametinib. inclusion of women and minorities: * both men and women, and members of all races and ethnic groups are eligible for this trial.

Keywords: phenformin dabrafenib trametinib braf/meki 15-318